Cancer is the second leading cause of death in the United States, with the various forms being attributed to one in four deaths. Approximately one in two men and one in three women will be diagnosed with an invasive cancer in their lifetime. Breast cancer is the leading type of cancer affecting women. It is estimated that breast cancer accounts for just over a quarter of all newly diagnosed cancer cases in women. Pancreatic cancer is the fourth leading cause of cancer deaths in the United States. Diagnosis is followed by a poor prognosis, with a five-year survival rate of only 5%. Worldwide, the survival rate for pancreatic cancer is only 1%. Gliomas, a type of brain cancer, account for more than 75% of all primary malignant brain tumors. The most common type of glioma, glioblastoma, is also the most severe. It is a highly aggressive cancer and continues to have a pool survival rate, with most cases becoming fatal within two years of diagnosis. The large number of cases and poor survival rates under current therapies necessitate the search for novel target therapies for cancer.
The Signal Transducers and Activators of Transcription (STAT) proteins are transcription factors that participate in cancer proliferation. STATs have been shown to relay signals from cytokines and growth factors. Constitutive activation of STATs has been found to contribute to oncogenesis. STAT3 in particular, is constitutively active in a wide variety of human malignancies; including breast and pancreatic cancer and glioblastoma. STAT3 is considered to be an oncogene due to its ability to promote malignancy. Experiments have shown that constitutively active STAT3 is sufficient for inducing cellular transformation. Further research shows a resistance to transformation in STAT3 deficient fibroblasts. Constitutively active STAT3 has also been shown to have the potential to alter the phenotype of non-malignant cells into malignant-like cells.
Persistent activation of STAT3 has been implicated in both the induction of cancer and processes promoting the survival of cancer. STAT3 activation occurs when the Tyrosine 705 (Tyr705) residue is phosphorylated, leading to dimerization and translocation from the cytoplasm to the nucleus. In the nucleus, STAT3 binding to target genes induces the transcription and up regulation of proliferation and anti-apoptotic associated proteins. Therefore, constitutive STAT3 signaling is involved in stimulating cell cycle progression and preventing apoptosis which both contribute to malignant progression. STAT3 has also been found to promote angiogenesis. In addition, persistently activated STAT3 plays a role in impairing both innate and adaptive immune responses by enhancing immunologic tolerance and enabling cancer cells to evade immune surveillance. Further, the survival of these tumors appears to depend on the presence of STAT3 signaling.
The implications of constitutive STAT3 signaling in tumors have presented it as a possible target for cancer treatment. Experiments aimed at blocking STAT3 signaling using dominant-negative STAT3, RNA interference, and STAT3 antisense oligonucleotides have been attempted. It was also determined that in normal cells, blocking STAT3 is neither harmful nor toxic to the cells. Given the oncogenic functions of STAT3, directly targeting STAT3 signaling represents a potential therapeutic approach to treating cancer.
The inventors herein have now shown, inter alia, that a new class of small molecules inhibits STAT3, resulting in apoptosis of cancer cells.
This invention therefore contributes effective therapeutic, diagnostic and prophylactic agents having increased positive results and fewer side effects. The invention also provides methods for making related compounds, formulations, compositions, kits, etc.